The present invention relates to novel antimicrobial agents and, more particularly, to a novel class of polymers which are designed to exert antimicrobial activity while being stable, non-toxic and avoiding development of resistance thereto. The present invention further relates to pharmaceutical compositions, medical devices and food preservatives containing such polymers and to methods of treating medical conditions associated with pathogenic microorganisms utilizing same.
Antibiotics, which are also referred to herein and in the art as antibacterial or antimicrobial agents, are natural substances of relatively small size in molecular terms, which are typically released by bacteria or fungi. These natural substances, as well as derivatives and/or modifications thereof, are used for many years as medications for treating infections caused by bacteria.
As early as 1928, Sir Alexander Fleming observed that colonies of the bacterium Staphylococcus aureus could be destroyed by the mold Penicillium notatum. His observations lead Fleming to postulate the existence and principle of action of antibiotic substances. It was established that the fungus releases the substance as a mean of inhibiting other organisms in a chemical warfare of microscopic scale. This principle was later utilized for developing medicaments that kill certain types of disease-causing bacteria inside the body. In 1940's Howard Florey and Ernst Chain isolated the active ingredient penicillin and developed a powdery form of the medicine.
These advancements had transformed medical care and dramatically reduced illness and death from infectious diseases. However, over the decades, almost all the prominent infection-causing bacterial strains have developed resistance to antibiotics.
Antibiotic resistance can result in severe adverse outcomes, such as increased mortality, morbidity and medical care costs for patients suffering from common infections, once easily treatable with antibiotics (Am. J. Infect. Control 24 (1996), 380-388; Am. J. Infect. Control 27 (1999), 520-532; Acar, J. F. (1997), Clin. Infect. Dis. 24, Suppl 1, S17-S18; Cohen, M. L. (1992), Science 257, 1050-1055; Cosgrove, S. E. and Carmeli, Y. (2003), Clin. Infect. Dis. 36, 1433-1437; Holmberg, S. D. et al. (1987), Rev. Infect. Dis. 9, 1065-1078) and therefore became one of the most recognized clinical problems of today's governmental, medicinal and pharmaceutical research (U.S. Congress, Office of Technology Assessment, Impacts of Antibiotic-Resistant Bacteria, OTA-H-629, Washington, D.C., U.S. Government Printing Office (1995); House of Lords, Science and Technology 7th Report: Resistance to Antibiotics and Other Antimicrobial Agents, HL Paper 81-II, session (1997-98); and Interagency Task Force on Antimicrobial Resistance, A Public Health Action Plan to Combat Antimicrobial Resistance. Part 1: Domestic issues).
Due to the limitations associated with the use of classical antibiotics, extensive studies have been focused on finding novel, efficient and non-resistance inducing antimicrobial/antibacterial agents.
Within these studies, a novel class of short, naturally occurring peptides, which exert outstanding antimicrobial/antibacterial activity, was uncovered.
These peptides, which are known as antimicrobial peptides (AMPs), are derived from animal sources and constitute a large and diverse family of peptides, which may serve as effective antimicrobial agents against antibiotic-resistant microorganisms (for recent reviews see, for example, Levy, O. (2000) Blood 96, 2564-2572; Mor, A. (2000) Drug Development Research 50, 440-447; Zasloff, M. (2002) New England Journal of Medicine 347, 1199-1200; Zasloff, M. (2002) Nature 415, 389-395; Zasloff, M. (2002) Lancet 360, 1116-1117). In the past 20 years, over 700 AMPs derived from various sources, from unicellular organisms to mammalians and including humans, have been identified (for recent reviews see, for example, Andreu, D. and Rivas, L. (1998) Biopolymers 47, 415-433; Boman, H. G. (2003) J. Intern. Med. 254, 197-215; Devine, D. A. and Hancock, R. E. (2002) Curr. Pharm. Des. 8, 703-714; Hancock, R. E. and Lehrer, R. (1998) Trends Biotechnol. 16, 82-88; Hancock, R. E. (2001) Lancet Infect. Dis. 1, 156-164; Hancock, R. E. and Rozek, A. (2002) FEMS Microbiol. Lett. 206, 143-149; Hoffmann, J. A. and Reichhart, J. M. (2002) Nat. Immunol. 3, 121-126; Lehrer, R. I. and Ganz, T. (1999) Curr. Opin. Immunol. 11, 23-27; Nicolas, P. and Mor, A. (1995) Annu. Rev. Microbiol. 49, 277-304; Nizet, V. and Gallo, R. L. (2002) Trends Microbiol. 10, 358-359; Shai, Y. (2002) Curr. Pharm. Des. 8, 715-725; Simmaco, M. et al. (1998) Biopolymers 47, 435-450; Tossi, A. et al. (2000) Biopolymers 55, 4-30; Tossi, A. and Sandri, L. (2002) Curr. Pharm. Des. 8, 743-761; Vizioli, J. and Salzet, M. (2002) Trends Pharmacol. Sci. 23, 494-496; Brogden, K. et al. (2003) Int. J. Antimicrob. Agents 22, 465-478 and Papagianni, M. (2003) Biotechnol. Adv. 21, 465-499).
AMPs are now recognized to have an important role in the innate host defense. They display a large heterogeneity in primary and secondary structures but share common features such as amphiphatic character and net positive charge. These features appear to form the basis for their cytolytic function. Ample data indicate that AMPs cause cells death by destabilizing the ordered structure of the cell membranes, although the detailed mechanism has not been fully understood yet (for recent reviews see, for example, Epand, R. M. et al. (1995), Biopolymers 37, 319-338; Epand, R. M. and Vogel, H. J. (1999), Biochim. Biophys. Acta 1462, 11-28; Gallo, R. L. and Huttner, K. M. (1998), J. Invest Dermatol. 111, 739-743; Gennaro, R. et al. (2002), Curr. Pharm. Des. 8, 763-778; Hansen, J. N. (1994), Crit Rev. Food Sci. Nutr. 34, 69-93; Huang, H. W. (1999), Novartis. Found. Symp. 225, 188-200; Hwang, P. M. and Vogel, H. J. (1998), Biochem. Cell Biol. 76, 235-246; Lehrer, R. I. et al. (1993), Annu. Rev. Immunol. 11, 105-128; Matsuzaki, K. (1999), Biochim. Biophys. Acta 1462, 1-10; Muller, F. M. et al. (1999), Mycoses 42 Suppl 2, 77-82; Nissen-Meyer, J. and Nes, I. F. (1997), Arch. Microbiol. 167, 67-77; Peschel, A. (2002), Trends Microbiol. 10, 179-186; Sahl, H. G. and Bierbaum, G. (1998), Annu. Rev. Microbiol. 52, 41-79; Shai, Y. (1995), Trends Biochem. Sci. 20, 460-464; and Yeaman, M. R. and Yount, N.Y. (2003), Pharmacol. Rev. 55, 27-55). It is assumed that disturbance in membrane structure leads to leakage of small solutes (for example K+, amino acids and ATP) rapidly depleting the proton motive force, starving cells of energy and causing cessation of certain biosynthetic processes (Sahl, H. G. and Bierbaum, G. (1998), Annu. Rev. Microbiol. 52, 41-79). This mechanism is consistent with the hypothesis that antimicrobial activity is not mediated by interaction with a chiral center and may thus significantly prevent antibiotic-resistance by circumventing many of the mechanisms known to induce resistance.
In addition to their direct well-documented cytolytic (membrane-disrupting) activity, AMPs also display a variety of interesting biological activities in various antimicrobial fields. Some AMPs were shown to activate microbicidal activity in cells of the innate immunity including leukocytes and monocyte/macrophages (Ammar, B. et al. (1998), Biochem. Biophys. Res. Commun. 247, 870-875; Salzet, M. (2002) Trends Immunol. 23, 283-284; Scott, M. G. et al. (2000), J. Immunol. 165, 3358-3365; and Scott, M. G. et al. (2002), J. Immunol. 169, 3883-3891). Many cationic peptides are endowed with lipopolysaccharide binding activity, thus suppress the production of inflammatory cytokines and protect from the cascade of events that leads to endotoxic shock (Chapple, D. S. et al. (1998), Infect. Immun. 66, 2434-2440; Elsbach, P. and Weiss, J. (1998), Curr. Opin. Immunol. 10, 45-49; Lee, W. J. et al. (1998), Infect. Immun. 66, 1421-1426; Giacometti, A. et al. (2003), J. Chemother. 15, 129-133; Gough, M. et al. (1996), Infect. Immun. 64, 4922-4927; and Hancock, R. E. and Chapple, D. S. (1999), Antimicrob. Agents Chemother. 43, 1317-1323). Antimicrobial genes introduced into the genome of plants granted the plant the resistance to pathogens by expressing the peptide (Alan, A. R. et al. (2004), Plant Cell Rep. 22, 388-396; DeGray, G. et al. (2001), Plant Physiol 127, 852-862; Fritig, B., Heitz, T. and Legrand, M. (1998), Curr. Opin. Immunol. 10, 16-22; Osusky, M. et al. (2000), Nat. Biotechnol. 18, 1162-1166; Osusky, M. et al. (2004), Transgenic Res. 13, 181-190; and Powell, W. A. et al. (2000), Lett. Appl. Microbiol. 31, 163-168).
On top of the ribosomally synthesized antimicrobial peptides that have been identified and studied during the last 20 years, thousands of de-novo designed AMPs, were developed (Tossi, A. et al. (2000), Biopolymers 55, 4-30). These de-novo designed peptides are comprised of artificially designed sequences and were produced by genetic engineering or by chemical peptide syntheses. The finding that various antimicrobial peptides, having variable lengths and sequences, are all active at similar concentrations, has suggested a general mechanism for the anti-bacterial activity thereof rather than a specific mechanism that requires preferred active structures (Shai, Y. (2002), Biopolymers 66, 236-248). Naturally occurring peptides, and de-novo peptides having artificially designed sequences, either synthesized by humans or genetically engineered to be expressed in organisms, exhibit various levels of antibacterial and antifungal activity as well as lytic activity toward mammalian cells. As a result, AMPs are attractive targets for bio-mimicry and peptidomimetic development, as reproduction of critical peptide biophysical characteristics in an unnatural, sequence-specific oligomer should presumably be sufficient to endow antibacterial efficacy, while circumventing the limitations associated with peptide pharmaceuticals (Latham, P. W. (1999), Nat. Biotechnol. 17, 755-757).
One of the challenges in designing new antimicrobial peptides relies on developing peptidomimetics that would have high specificity toward bacterial or fungal cells, and consequently, would allow better understanding of the mechanism underlying the peptide lytic specificity, i.e., discrimination between cell membranes. Structure-activity relationships (SAR) studies on AMPs typically involve the systematic modification of naturally occurring molecules or the de-novo design of model peptidomimetics predicted to form amphiphatic alpha-helices or beta-sheets, and the determination of structure and activity via various approaches (Tossi, A. et al. (2000), Biopolymers 55, 4-30), as follows:
Minimalist methods for designing de-novo peptides are based on the requirement for an amphiphatic, alpha-helical or beta-sheet structure. The types of residues used are generally limited to the basic, positively charged amino acids lysine or arginine, and one to three of the hydrophobic residues alanine, leucine, isoleucine, glycine, valine, phenylalanine, or tryptophan (Blazyk, J. et al. (2001), J. Biol. Chem. 276, 27899-27906; Epand, R. F. et al. (2003), Biopolymers 71, 2-16; Hong, J. et al. (1999), Biochemistry 38, 16963-16973; Jing, W. et al. (2003), J. Pept. Res. 61, 219-229; Ono, S. et al. (1990), Biochim. Biophys. Acta 1022, 237-244; and Stark, M. et al. (2002), Antimicrob. Agents Chemother. 46, 3585-3590). While these approaches may lead to the design of potent antimicrobial agents, subtleties to the sequence of AMPs that may have been selected for by evolution are not considered and their absence may lead to a loss of specificity.
Sequence template methods for designing and synthesizing amphiphatic AMPs typically consists of extracting sequence patterns after comparison of a large series of natural counterparts. The advantage of this method, as compared with conventional sequence modification methods, is that it reduces the number of peptides that need to be synthesized in order to obtain useful results, while maintaining at least some of the sequence based information. As discussed hereinabove, the latter is lost in minimalist approaches (Tiozzo, E. et al. (1998), Biochem. Biophys. Res. Commun. 249, 202-206).
Sequence modification method includes all of the known and acceptable methods for modifying natural peptides, e.g., by removing, adding, or replacing one or more residues, truncating peptides at the N- or C-termini, or assembling chimeric peptides from segments of different natural peptides. These modifications have been extensively applied in the study of dermaseptins, cecropins, magainins, and melittins in particular (Scott, M. G. et al. (2000), J. Immunol. 165, 3358-3365; Balaban, N. et al. (2004), Antimicrob. Agents Chemother. 48, 2544-2550; Coote, P. J. et al. (1998), Antimicrob. Agents Chemother. 42, 2160-2170; Feder, R. et al. (2000), J. Biol. Chem. 275, 4230-4238; Gaidukov, L. et al. (2003), Biochemistry 42, 12866-12874; Kustanovich, I. et al. (2002), J. Biol. Chem. 277, 16941-16951; Mor, A. and Nicolas, P. (1994) J. Biol. Chem. 269, 1934-1939; Mor, A. et al. (1994), J. Biol. Chem. 269, 31635-31641; Oh, D. et al. (2000), Biochemistry 39, 11855-11864; Patrzykat, A. et al. (2002), Antimicrob. Agents Chemother. 46, 605-614; Piers, K. L. and Hancock, R. E. (1994) Mol. Microbiol. 12, 951-958; and Shepherd, C. M. et al. (2003), Biochemistry 370, 233-243).
The approaches described above have been applied in many studies aiming at designing novel AMPs. In these studies, the use of alpha-helix and/or beta-sheet inducing building blocks, the use of the more flexible beta-amino acid building blocks, the use of mixed D- and L-amino acid sequences and the use of facially amphiphilic arylamide polymers, have all demonstrated the importance of induced amphiphatic conformations on the biological activity of AMPs.
Antimicrobial peptides can act in synergy with classical antibiotics, probably by enabling access of antibiotics into the bacterial cell (Darveau, R. P. et al. (1991), Antimicrob. Agents Chemother. 35, 1153-1159; and Giacometti, A. et al. (2000), Diagn. Microbiol. Infect. Dis. 38, 115-118). Other potential uses include food preservation (Brul, S. and Coote, P. (1999), Int. J. Food Microbiol. 50, 1-17; Yaron, S., Rydlo, T. et al. (2003), Peptides 24, 1815-1821; Appendini, P. and Hotchkiss, J. H. (2000), J. Food Prot. 63, 889-893; and Johnsen, L. et al. (2000), Appl. Environ. Microbiol. 66, 4798-4802), imaging probes for detection of bacterial or fungal infection loci (Welling, M. M. et al. (2000), Eur. J. Nucl. Med. 27, 292-301; Knight, L. C. (2003), Q. J. Nucl. Med. 47, 279-291; and Lupetti, A. et al. (2003), Lancet Infect. Dis. 3, 223-229), antitumor activity (Baker, M. A. et al. (1993), Cancer Res. 53, 3052-3057; Jacob, L. and Zasloff, M. (1994), Ciba Found. Symp. 186, 197-216; Johnstone, S. A. et al. (2000), Anticancer Drug Des 15, 151-160; Moore, A. J. et al. (1994), Pept. Res. 7, 265-269; and Papo, N. and Shai, Y. (2003), Biochemistry 42, 9346-9354), mitogenic activity (Aarbiou, J. et al. (2002), J. Leukoc. Biol. 72, 167-174; Murphy, C. J. et al. (1993), J. Cell Physiol 155, 408-413; and Gudmundsson, G. H. and Agerberth, B. (1999), J. Immunol. Methods 232, 45-54) and lining of medical/surgical devices (Haynie, S. L. et al. (1995), Antimicrob. Agents Chemother. 39, 301-307).
However, while the potential of AMPs as new therapeutic agents is well recognized, the use of the presently known AMPs is limited by lack of adequate specificity, and optional systemic toxicity (House of Lords, Science and Technology 7th Report: Resistance to antibiotics and other antimicrobial agents. HL Paper 81-II, session, 1997-98; and Alan, A. R. et al. (2004), Plant Cell Rep. 22, 388-396). Thus, there is a clear need for developing new antimicrobial peptides with improved specificity and toxicity profile.
Moreover, although peptides are recognized as promising therapeutic and antimicrobial agents, their use is severely limited by their in vivo and ex vivo instability and by poor pharmacokinetics. Peptides and polypeptides are easily degraded in oxidative and acidic environments and therefore typically require intravenous administration (so as to avoid, e.g., degradation in the gastrointestinal tract). Peptides are further broken down in the blood system by proteolytic enzymes and are rapidly cleared from the circulation. Moreover, peptides are typically characterized by poor absorption after oral ingestion, in particular due to their relatively high molecular mass and/or the lack of specific transport systems. Furthermore, peptides are characterized by high solubility and therefore fail to cross biological barriers such as cell membranes and the blood brain barrier, but exhibit rapid excretion through the liver and kidneys. The therapeutic effect of peptides is further limited by the high flexibility thereof, which counteracts their receptor-affinity due to the steep entropy decrease upon binding and a considerable thermodynamic energy cost. In addition, peptides are heat and humidity sensitive and therefore their maintenance requires costly care, complex and inconvenient modes of administration, and high-cost of production and maintenance. The above disadvantages impede the use of peptides and polypeptides as efficient drugs and stimulate the quest for an alternative, which oftentimes involves peptidomimetic compounds.
Peptidomimetic compounds are modified polypeptides which are designed to have a superior stability, both in vivo and ex vivo, and yet at least the same receptor affinity, as compared with their parent peptides. In order to design efficacious peptidomimetics, an utmost detailed three-dimensional understanding of the interaction with the intended target is therefore required.
One method attempting at achieving the above goal utilizes synthetic combinatorial libraries (SCLs), a known powerful tool for rapidly obtaining optimized classes of active compounds. Thus, a number of novel antimicrobial compounds ranging from short peptides to small heterocyclic molecules have been identified from SCLs (Blondelle, S. E. and Lohner, K. (2000), Biopolymers 55, 74-87).
Several families of naturally occurring modified peptides which exhibit strong antimicrobial activity, have been uncovered in many organisms. These compounds, and their effective chemical alterations, have proposed a lead towards a general solution to the challenge of creating an antimicrobial compound devoid of the disadvantages associated with natural AMPs.
Thus, for example, naturally occurring short antimicrobial peptides characterized by a lipophilic acyl chain at the N-terminus were uncovered in various microorganisms (Bassarello, C. et al. (2004), J. Nat. Prod. 67, 811-816; Peggion, C., et al. (2003), J. Pept. Sci. 9, 679-689; and Toniolo, C. et al. (2001), Cell Mol. Life Sci. 58, 1179-1188). Acylation of AMPs was hence largely used as a technique to endow AMPs with improved antimicrobial characteristics (Avrahami, D. et al. (2001), Biochemistry 40, 12591-12603; Avrahami, D. and Shai, Y. (2002), Biochemistry 41, 2254-2263; Chicharro, C. et al. (2001), Antimicrob. Agents Chemother. 45, 2441-2449; Chu-Kung, A. F. et al. (2004), Bioconjug. Chem. 15, 530-535; Efron, L. et al. (2002), J. Biol. Chem. 277, 24067-24072; Lockwood, N. A. et al. (2004), Biochem. J. 378, 93-103; Mak, P. et al. (2003), Int. J. Antimicrob. Agents 21, 13-19; and Wakabayashi, H. et al. (1999), Antimicrob. Agents Chemother. 43, 1267-1269). However, some studies indicate that attaching a hydrocarbon chain to the peptide, results in only marginal increase in the affinity of the lipopeptide to the membrane (Epand, R. M. (1997), Biopolymers 43, 15-24).
One family of AMPs capable of alluding towards the main goal is the family of dermaseptins. Dermaseptins are peptides isolated from the skin of various tree frogs of the Phyllomedusa species (Brand, G. D. et al. (2002), J. Biol. Chem. 277, 49332-49340; Charpentier, S. et al. (1998), J. Biol. Chem. 273, 14690-14697; Mor, A. et al. (1991), Biochemistry 30, 8824-8830; Mor, A. et al. (1994), Biochemistry 33, 6642-6650; Mor, A. and Nicolas, P. (1994), Eur. J. Biochem. 219, 145-154; and Wechselberger, C. (1998), Biochim. Biophys. Acta 1388, 279-283). These are structurally and functionally related cationic peptides, typically having 24-34 amino acid residues. Dermaseptins were found to exert rapid cytolytic activity, from seconds to minutes, in vitro, against a variety of microorganisms including viruses, bacteria, protozoa, yeast and filamentous fungi (Coote, P. J. et al. (1998), Antimicrob. Agents Chemother. 42, 2160-2170; Mor, A. and Nicolas, P. (1994), J. Biol. Chem. 269, 1934-1939; Mor, A. et al. (1994), J. Biol. Chem. 269, 31635-31641; Mor, A. and Nicolas, P. (1994), Eur. J. Biochem. 219, 145-154; Belaid, A. et al. (2002), J. Med. Virol. 66, 229-234; De Lucca, A. J. et al. (1998), Med. Mycol. 36, 291-298; Hernandez, C. et al. (1992), Eur. J. Cell Biol. 59, 414-424; and Mor, A. et al. (1991), J. Mycol. Med 1, 5-10) as well as relatively inaccessible pathogens such as intracellular parasites (Efron, L. et al. (2002), J. Biol. Chem. 277, 24067-24072; Dagan, A. et al. (2002), Antimicrob. Agents Chemother. 46, 1059-1066; Ghosh, J. K. et al. (1997), J. Biol. Chem. 272, 31609-31616; and Krugliak, M. et al. (2000), Antimicrob. Agents Chemother. 44, 2442-2451).
Since dermaseptins portray the biodiversity existing in a very large group of antimicrobial peptides in terms of structural and biological properties, they serve as a general model system for understanding the function(s) of cationic antimicrobial peptides.
The 28-residue peptide dermaseptin S4 is known to bind avidly to biological membranes and to exert rapid cytolytic activity against a variety of pathogens as well as against erythrocytes (Mor, A. et al. (1994), J. Biol. Chem. 269(50): 31635-41).
In a search for an active derivative (peptidomimetic) of S4, a 28-residue derivative in which the amino acid residues at the fourth and twentieth positions were replaced by lysine residues, known as K4K20-S4, and two short derivatives of 16 and 13 residues in which the amino acid residue at the fourth position was replaced by a lysine residue, known as K4-S4(1-16) and K4-S4(1-13), respectively, were prepared and tested for the inhibitory effect thereof (Feder, R. et al. (2000), J. Biol. Chem. 275, 4230-4238). The minimal inhibitory concentrations (MICs) of these derivatives for 90% of the 66 clinical isolates tested (i.e., MIC90 for S. aureus, P. aeruginosa and E. coli), varied between 2 and 8 μg/ml for the various species, whereby the 13-mer derivative K4-S4(1-13) was found to be significantly less hemolytic when incubated with human erythrocytes, as compared with similarly active derivatives of magainin and protegrin, two confirmed antimicrobial peptide families (Fahrner, R. L. et al. (1996), Chem. Biol. 3(7): 543-50; Zasloff, M. et al. (1988), Proc. Natl. Acad. Sci. USA 85(3): 910-3; Yang L. et al. (2000), Biophys. J, 79 2002-2009). Additional studies further confirmed that short, lysine-enriched S4 derivatives, are promising anti-microbial agents by being characterized by reduced toxicity and by showing efficacy also after pre-exposure of the subjects thereto.
N-terminal acylation of the C-terminally truncated 13-mer S4 derivative K4-S4(1-13) also resulted in reduced hemolytic activity, whereby several derivatives, such as its aminoheptanoyl derivative, displayed potent and selective activity against the intracellular parasite, i.e., increased antiparasitic efficiency and reduced hemolysis. These studies indicate that increasing the hydrophobicity of anti-microbial peptides enhance their specificity, presumably by allowing such AMPs to act specifically on the membrane of intracellular parasites and thus support a proposed mechanism according to which the lipopeptide crosses the host cell plasma membrane and selectively disrupts the parasite membrane(s).
Overall, the data collected from in-vitro and in-vivo experiments indicated that some dermaseptin derivatives could be useful in the treatment of a variety of microbial-associated conditions including infections caused by multidrug-resistant pathogens. These agents were found highly efficacious, and no resistance was appeared to develop upon their administration. Nevertheless, the therapeutic use of these agents is still limited by the in vivo and ex vivo instability thereof, by poor pharmacokinetics, and by other disadvantageous characteristics of peptides, as discussed hereinabove.
In conclusion, most of the presently known antimicrobial peptides and peptidomimetics are of limited utility as therapeutic agents despite their promising antimicrobial activity. The need for compounds which have AMP characteristics, and are devoid of the limitations associated with AMPs is still present, and the concept of providing chemically and metabolically-stable active compounds in order to achieve enhanced specificity and hence enhanced clinical selectivity has been widely recognized.
There is thus a widely recognized need for, and it would be highly advantageous to have, novel, metabolically-stable, non-toxic and cost-effective antimicrobial agents devoid of the above limitations.